Scotton, Christopher John; (2002) Chemokines and their receptors in ovarian cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The chemokine/chemokine receptor network was investigated in solid human ovarian cancer and cancer ascites. In solid tumours, CC chemokine receptor mRNA was generally absent, the exception being CCR1 which was detected in 75% of patients. CCR1 mRNA localised to macrophages and lymphocytes and there was a correlation between the number of CD8+ and CCR1 expressing cells. mRNA for the CC chemokines CCL2, 3, 4, 5, 8 and 22 was expressed in a majority of biopsies. In a monocytic cell line in vitro, CCR1 mRNA expression was increased five-fold by hypoxia, which is a common feature of the tumour microenvironment. In ascites, there were variable numbers of tumour cells, macrophages and CD3+ T cells (predominantly CD4+) and mRNA was found for all the CC chemokines and receptors investigated. A direct correlation was found between the CCL5 protein concentration and the extent of the CD3+ T cell infiltrate in ascites. The predominance of CD4+ T cells in ascites may be associated with their chemokine receptor expression profile. The possibility that chemokine gradients could influence migration of human ovarian epithelial tumour cells was also examined. Of 14 chemokine receptors investigated, only CXCR4 was expressed on ovarian cancer cells. CXCR4 mRNA localised to a subpopulation of tumour cells in solid ovarian tumour biopsies. Ovarian cancer cell lines and tumour cells isolated from ascites expressed CXCR4 protein. The CXCR4 ligand, CXCL12, was found in ascites from 63 patients. Cell surface CXCR4 protein was functional on the ovarian cancer cell lines: stimulation with CXCL12 elicited an intracellular calcium flux; directed migration and invasion; and caused changes in integrin expression. CXCL12 also stimulated proliferation and/or survival of the ovarian cancer cell lines. Signalling downstream of CXCR4 involved activation of Akt/PKB and ERK1/2. CXCR4 may influence cell migration and survival in the peritoneum, a major route for ovarian cancer spread. Chemokine receptor antagonists may be of therapeutic benefit in ovarian cancer. CCR1 receptor antagonists could affect the leukocyte infiltrate, while CXCR4 receptor antagonists could inhibit metastasis.

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